The project is designed to determine if haploinsufficiency of HSPA9 contributes to the development of myelodysplastic syndrome (MDS) and subsequent transformation to acute myeloid leukemia (AML). HSPA9 is located on chromosome 5 in a region that is commonly deleted in patients with MDS (del(5q)). This deletion is associated with the development of a highly chemotherapy-resistant form of AML. In vitro data shows that a reduction in HSPA9 levels disrupts erythroid development, increases apoptosis, and alters cell cycle progression, all hallmarks of MDS. In Specific Aim 1, we will comprehensively characterize hematopoiesis in Hspa9 heterozygous mice using standard methods. This will establish the in vivo consequences of Hspa9 haploinsufficiency on hematopoiesis and develop a novel model of del(5q)-related MDS that could be used for mechanistic and therapeutic studies. Specific Aim 2 will determine if loss of Hspa9 is sufficient for AML development and will identify genes that cooperate with Hspa9 to cause AML. For this aim, we will age out a cohort of heterozygous mice and monitor them for disease. We will also induce identifiable secondary mutations in another cohort of mice by viral insertional mutagenesis. Identification of cooperating mutations may lend insight into commonly altered pathways and provide avenues for therapeutic prevention of AML transformation. These goals correlate well with the mission of the National Cancer Institute to promote research investigating the cause, prevention, and treatment of cancer. PUBLIC HEALTH RELEVANCE: Myelodysplastic syndromes (MDS) are characterized by low blood counts with an increased risk of developing leukemia and as the population ages, the prevalence of the disease increases. Our goal is to improve the outcomes of patients with MDS by identifying and characterizing the mutated genes that cause MDS.